Background: Although evidence suggests the effectiveness of cognitive and behaviorally oriented family therapies for schizophrenia, no specific randomized study has been carried out on Systemic Family Therapy (SFT). The purpose of this longitudinal prospective study was to evaluate the clinical effectiveness of SFT in the treatment of patients suffering from schizophrenia, as compared with a control case sample composed of patients undergoing routine psychiatric treatment. The study included a 2-year follow-up period and was conducted following the Milan School model. Methods: The case sample in the study was made up of 20 patients treated with SFT associated with routine psychiatric treatment, and 20 patients undergoing routine psychiatric treatment alone. Both groups of patients were re-evaluated at the end of treatment (T1) and 12 months after the end of treatment (T2) to assess the clinical course of the illness. Results: At the end of the follow-up period, we noticed an improved clinical course and a better pharmacological compliance in the group of patients treated with SFT. In the experimental case sample, 3 subjects (15%) had relapsed, compared to 13 patients (65%) in the control group (p = 0.03). No significant difference was found in the 2nd year of follow-up. Conclusions: Our study provides an innovative contribution with regard to the evaluation of the clinical effectiveness of SFT in the treatment of schizophrenic patients. The clinical results were significant, and we thus feel justified in continuing to use this type of therapy in integrated interventions involving schizophrenic patients.